Oxidative metabolism and pharmacokinetics of the EGFR inhibitor BIBX1382 in chimeric NOG-TKm30 mice transplanted with human hepatocytes

Drug Metab Pharmacokinet. 2021 Dec:41:100419. doi: 10.1016/j.dmpk.2021.100419. Epub 2021 Aug 24.

Abstract

The epidermal growth factor receptor inhibitor BIBX1382 has failed in drug development because of poor oral exposure and low bioavailability associated with its extensive metabolism by aldehyde oxidase (AOX) in humans. In this study, we investigated the metabolic profiles and pharmacokinetics of BIBX1382 in chimeric NOG-TKm30 mice with humanized liver (humanized liver mice). After intravenous and oral BIBX1382 administration, increased plasma clearance and decreased oral exposure together with high production of the predominant oxidative metabolite (M1, BIBU1476) and secondary oxidized metabolite (M2) were observed in humanized liver mice. Extensive oxidation rates of BIBX1382 were observed in hepatocytes from humanized liver mice and were suppressed by the typical human AOX1 inhibitors raloxifene and hydralazine. Liver cytosolic fractions from humans, humanized liver mice, cynomolgus monkeys, minipigs, and guinea pigs, but not fractions from dogs, rabbits, rats, and mice, displayed high BIBX1382 clearance and resulted in oxidative metabolite production. These results indicate that humanized liver mice have human-type AOX activity based on the transplanted human liver AOX1 function. Humanized liver mice can be considered an important animal model for understanding the metabolism and pharmacokinetics of AOX drug substrates.

Keywords: Aldehyde oxidase; BIBX1382; Drug metabolism; Hu-liver cell; Humanized liver mouse.

MeSH terms

  • Aldehyde Oxidase* / genetics
  • Aldehyde Oxidase* / metabolism
  • Animals
  • Dogs
  • ErbB Receptors / metabolism
  • Guinea Pigs
  • Hepatocytes* / metabolism
  • Humans
  • Liver / metabolism
  • Mice
  • Oxidative Stress
  • Rabbits
  • Rats
  • Swine
  • Swine, Miniature / metabolism

Substances

  • Aldehyde Oxidase
  • EGFR protein, human
  • ErbB Receptors